Hepatitis B virus X protein induces expression of alpha-fetoprotein and activates PI3K/mTOR signaling pathway in liver cells.
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We found that HBV induced the expression of AFP before that of oncogenes, e.g., Src, Ras and chemokine (C-X-C motif) receptor 4 (CXCR4), and AFP activated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in HBV-related HCC tissues and in human liver cells transfected with HBx.Cytoplasmic AFP interacted with and inhibited phosphatase and tensin homolog deleted on chromosome 10 (PTEN), activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and promoting mTOR-mediated stimulation of the transcription factor hypoxia inducible factor-1α (HIF-1α), and therefore led to the activation of the promoters of Src, CXCR4, and Ras genes.On the contrary, reduced expression of AFP by siRNA resulted in the repression of p-mTOR, pAKT, Src, CXCR4, and Ras in human malignant liver cells.
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PubMed Central - PubMed
Affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.
ABSTRACT
The hepatitis B virus (HBV)-X protein (HBx) induces malignant transformation of liver cells, and elevated expression of alpha-fetoprotein (AFP) is a significant biomarker of hepatocarcinogenesis. However, the role of AFP in HBV-related hepatocarcinogenesis is unclear. In this study, we investigated the regulatory impact of AFP expression on HBx-mediated malignant transformation of human hepatocytes. We found that HBV induced the expression of AFP before that of oncogenes, e.g., Src, Ras and chemokine (C-X-C motif) receptor 4 (CXCR4), and AFP activated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in HBV-related HCC tissues and in human liver cells transfected with HBx. Cytoplasmic AFP interacted with and inhibited phosphatase and tensin homolog deleted on chromosome 10 (PTEN), activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and promoting mTOR-mediated stimulation of the transcription factor hypoxia inducible factor-1α (HIF-1α), and therefore led to the activation of the promoters of Src, CXCR4, and Ras genes. On the contrary, reduced expression of AFP by siRNA resulted in the repression of p-mTOR, pAKT, Src, CXCR4, and Ras in human malignant liver cells. Taken together, for the first time our study indicates that HBx-induced AFP expression critically promote malignant transformation in liver cells through the activation of PI3K/mTOR signaling. No MeSH data available. Related in: MedlinePlus |
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Figure 2: Effects of pcDNA3.1-HBx on the expression of AFP, Src, CXCR4, Ras, pAKT(Ser473), and p-mTOR(Ser2448) in liver cells(A) L-02 and CHL liver cells were transfected with pcDNA3.1-HBx and expression of HBx was measured 48 hours later by Western blotting. (B) Expression of Src, CXCR4, Ras, pAKT(Ser473), and p-mTOR(Ser2448) was measured by Western blotting 1, 7, 14, 21, and 28 days after transfection. Results are from one representative experiment of three. Mentions: We transfected a vector expressing the HBV protein HBx, pcDNA3.1-HBx, into human liver cell lines L-02 and CHL and measured the impact of pcDNA3.1-HBx on the expression of AFP and the oncogenes Src, CXCR4, and Ras. The pcDNA3.1-HBx-mediated induction of HBx expression in L-02 and CHL cells was evident 2 days after transfection and remained elevated between 7 and 28 days after transfection (Figure 2A). Expression of AFP was emerged after transfected with pcDNA3.1-HBx for 7 days and persisted increasing after 28 days. Expression of CXCR4 and Ras was enhanced 7 day after transfection and increased for 28 days in both L-02 and CHL cells (Figure 2B). The expressions of AFP and CXCR4 were further confirmed at the mRNA levels by quantitative RT-PCR analysis (Supplementary Figure 1B). Src expression was elevated 14 days after transfection in both L-02 and CHL cells (Figure 2B). |
View Article: PubMed Central - PubMed
Affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.
No MeSH data available.